More than twenty percent of the adult population present the symptoms and complaints of hypertension. In most cases of systemic hypertension, the pathogenesis of the disease is obscure and therapy is directed only toward the correction of the abnormal blood pressure.
Although such an empirical approach to the management of a serious disease state is far from ideal, it is clear that manometric success per se does favorably affect prognosis. It has been established that when the systolic and/or diastolic blood pressures are at the upper extreme of the presently accepted normal range, the risk of death of cardiovascular disease is greater for the patient and when the blood pressure rises above the normal range, the patient threat increases inordinately. Simply lowering the diastolic pressure to below 105 mm Hg. has been found to reduce the morbidity and mortality arising from a variety of cardiovascular complications.
Current therapy of hypertension is directed essentially toward the reduction of systemic blood pressure and because of such an omnibus approach no present single agent or treatment regimen has been found to be specific to either cure this disease or even to be consistently symptomatically effective in lowering blood pressure in the hypertensive patient.
Diuretic agents are among the most commonly used drugs in present day therapy to achieve a lowering of blood pressure and among the different diuretic agents used in the treatment of hypertension, the thiazide class of diuretic drugs is perhaps the most commonly administered diuretic substance. In its simplistic definition, diuretic substances are agents which increase the volume of urine output. However, by common usage the term diuresis has assumed two special connotations which comprise first, an increased urine volume output and secondly, a net loss of solute and water. While the renal physiology affecting these separate actions are independent of one another, there is an interaction between these effects which is reflected in the overall therapeutic response.
The thiazide diuretics are understood to act on the proximal kidney tubule to inhibit both water reabsorption together with sodium and chloride ions. The enhanced sodium ion load presented to the distal tubule segment also causes an increased loss of potassium ion and requires potassium supplementation, a major problem of diuretic therapy.
The composition of urine is the result of a complex series of secretory and reabsorptive functions performed by the renal tubule, the functional unit of the kidneys. Virtually all substances present in plasma are transported through the tubules wherein both excretory filtration as well as reabsorption occurs. The amount of a solute excreted into urine and the proportion reabsorbed in the tubule depend upon many diverse properties of the solute, as well as the integrity of kidney physiology.
In general, the rate of excretion of a solute through the kidneys will be proportional to its concentration in plasma. Substances that are in water-soluble polar form are excreted in urine, whereas compounds which are in a non-polar lipid-soluble form will be reabsorbed and recycled so that their therapeutic effect will persist as a function of the metabolic rate in the various systemic tissues. In the presence of high volume urine output, the blood levels of a drug are reduced, thereby lowering the pharmacologic intensity of the systemic effect.
At low urinary flow rates, a high tubular diffusion substance will be readily reabsorbed to retain or enhance its effect. Thus as urine flow increases under diuresis, back-diffusion becomes less significant and excretion is enhanced, to minimize and even negate important pharmacologic actions.
It has been recognized that the pH of urine dramatically influences the diffusion reabsorption rate for a particular compound. The extent to which a weak acid or weak base will be reabsorbed from renal tubular fluid will depend on its ionization constant, and the inherent lipid solubility of the molecular species. The lipid form of a compound is more readily reabsorbed and is less subject to excretion in urine.
As the pH of the urine decreases, a large fraction of a weak acid will be converted to the undissociated lipid form of the compound and conversely, as the pH rises, a larger fraction of a weak base will be present in the undissociated state. Thus weak acids are preferentially reabsorbed in the kidney at an acid pH value, but are excreted more readily as the urine pH becomes more alkaline, while bases are more readily excreted in an acid urine than when it is more alkaline.
These physiologic considerations of urinary excretion and reabsorption to maintain a constant plasma level become most significant for those compounds whose separate pharmacologic actions occur at particular threshold levels. High plasma threshold-level actions are obscured and even negated by a rapid depletion of the agent through increased urinary flow and solute loss. Increasingly large doses of a drug are then required to obtain the desired effect with the consequent occurrence of serious, noxious, unwanted side effects, in order to achieve the desired high threshold effect in the presence of diuresis.
Experimental studies have demonstrated that the bi-diretional transport of plasma solutes is also influenced by a selective competition at the appropriate tubular receptive site for either excretion or reabsorption and results in either an increased or decreased excretion of a plasma solute with a corresponding variation in the intensity of its pharmacologic response. The clinical finding that a thiazide diuretic drug may cause hyperuricemia, although it rarely exacerbates an acute attack of gout, suggests that this class of diuretic substances exerts a competitive biphasic action on uric acid secretion. Hyperuricemia induced in the course of high volume diuretic therapy is becoming more prevalent and is gaining increased concern.
In other recent studies, it was shown that the saluretic effect of hydrochlorothiazide is prevented by the prior administration of the compound, probenecid, but if the thiazide is given first, saluresis occurs even though the appearance of the thiazide in the urine is delayed by the later administration of probenecid. This effect demonstrates that the excretion of the thiazides occurs at a site other than that for saluresis and that the plasma concentration of the thiazide causing a systemic response, may be unrelated to the diuretic saluresis observed. While saluresis may be high, the systemic action of the thiazides may be low or even absent.
The transport of sodium ion is particularly important in the kidney management of hypertension. In the course of its normal activity the kidney regulates electrolyte balance primarily through the reabsorption of water and the sodium ion. The reabsorption of sodium salts is accomplished with the back diffusion of large amounts of water. The magnitude of such reabsorptive process is readily seen from the fact that approximately 180 liters of glomerural urinary filtrate is formed within a twenty-four hour period, but about 178-179 liters of which are reabsorbed, carrying with it nearly 1.2 kilograms of salt. This reabsorption of electrolytes and water is so carefully controlled that the osmolality, pH and electrolyte content of plasma and cellular fluids are constantly maintained within extremely narrow normal limits.
Reabsorption of sodium ions and corresponding amounts of water to render tubular fluid hypotonic is known to occur in the loop of Henle. Here, a process similar to that occurring in the proximal renal tubule takes place to provide a final adjustment of the electrolyte excretion in urine. Both sodium ion and water are reabsorbed but the reabsorption of electrolytes and water along the tubule is inversely related to the volume of urine excreted.
When large amounts of urine are excreted, as in the presence of potent diuretic substances, correspondingly increased amounts of sodium and other electrolytes are also excreted. It is important to recognize that thiazide diuretic agents have been shown to be without effect on the loop of Henle, and exert their saluretic effect through an action at another reabsorptive site as well as by high urine volume excretion.
There is a general agreement of the adverse relationship between sodium ion content in the blood and hypertension. This has given rise to the general therapeutic concept for a need to reduce plasma sodium ion levels. In fact, the antihypertensive action of the thiazide diuretics was originally thought to simulate the beneficial effects produced by low salt diets for the hypertensive patient through renal elimination of salt. However, long term balance studies have not supported the hypothesis that chronic sodium depletion adequately explains long term antihypertensive effects observed observed for this class of compounds. Newer experimental studies have indicated that thiazides may decrease the effects of catecholamines which would alter the electrolyte content of the vascular wall. However, an antihypertensive action occurring apart from the high volume diuresis has not been clinically demonstrated for diuretic agents and current therapy with diuretic drugs is based solely upon their respective diuretic potency and saluretic action.
In the course of development of a unified concept of the relationship between sodium ion reabsorption; acidification of urine and the role of carbonic hydrase inhibition in hydrogen ion and bicarbonate transport in the kidney the synthesis of potent chemical agents acting on the kidney, was accomplished. Chlorothiazide, the first thiazide compound synthesized, was shown to be a potent diuretic and saluretic agent. Following the clinical introduction of chlorothiazide, an expanded series of structurally related chemical compounds were synthesized, all having essentially the same pharmacology, but differing diuretic potencies.
Analogues to the earlier series of thiazide diuretic compounds, in which the heterocyclic ring was saturated (hydrothiazides) were subsequently prepared and shown to possess significantly greater diuretic potency. However, all thiazide compounds have common structural relationships and all are used on the basis of their common diuretic property. The structural similarities of the group of thiazide diuretic agents, together with their comparative properties are presented in Table I.
The natriuretic effect obtained with the separate thiazide derivatives is essentially similar for all thiazide compounds. Although the average daily diuretic does for the thiazide compounds ranges from 2000 mg. (2 grams) of chlorothiazide to about 2 mg. for cyclopenthiazide and cyclothiazide, there is little difference in either the magnitude of diuresis or saluresis obtained among the various compounds. The more potent agents have a relatively greater chloretic activity and may even cause a hypochloretic alkalosis in some patients. All thiazide compounds cause potassium loss which is directly related to the magnitude of sodium ion excreted rather than to the particular thiazide employed or its structure.
TABLE I __________________________________________________________________________ STRUCTURE, ACTIVITY, AVERAGE MINIMUM DIURETIC DOSE OF THIAZIDE DIURETIC COMPOUNDS Prototype Structures ##STR1## ##STR2## Carbonic** Approx.*** Daily Thiazide Group of Substituents in Position* Anhydrase Natriuretic Diuretic Compounds 2 3- 5- 6- Inhibition Activity Dose (mg) __________________________________________________________________________ Chlorothiazide H H H Cl 7.6 1 2000 Flumethiazide H H H CF.sub.3 0.3 1 200 Benzthiazide H CH.sub.2 SCH.sub.2 C.sub.6 H.sub.5 H Cl 36.0 10 200 Hydrochlorothiazide H H H Cl 0.6 10 200 Hydroflumethiazide H H H CF.sub.3 0.08 10 200 Bendroflumethiazide H CH.sub.2 C.sub.6 H.sub.5 H CF.sub.3 0.04 100 20 Polythiazide CH.sub.3 CH.sub.2 SCH.sub.2 CF.sub.3 H Cl 2.0 200 8 Methyclothiazide CH.sub.3 CH.sub.2 Cl H Cl 2.5 100 10 Trichlormethiazide H CHCl.sub.2 H Cl 0.25 200 8 Cyclothiazide H (5-norbornen-2-yl) H Cl 0.5 500 2 Cyclopenthiazide H cyclopentylmethyl H Cl 1.0 1000 2 __________________________________________________________________________ *The 7position is always substituted with a sulfonamide group in all thiazide compounds. **Carbonic Anhydrase Inhibition values are stated as a ratio of sulfonilamide having a value of 1. ***The natriuretic activity reported is based upon a comparison with chlorothiazide having a value of 1.
All of the thiazide derivatives inhibit carbonic anhydrase to some extent, but this inhibitory activity does not correlate with the compound's activity as a diuretic agent. Cyclopenthiazide is only 1/10th as active as chlorothiazide as a carbonic anhydrase inhibitor but is a thousand times more potent as a diuretic and natriuretic agent. On the other hand, the carbonic anhydrase inhibition observed for the different thiazide compounds does not correlate with their ability to block bicarbonate reabsorption. Benzthiazide is a relatively potent carbonic anhydrase inhibitor, but it does not cause an appreciable clinical alkalinization of urine but rather produces the excretion of nearly equivalent amounts of sodium ion and chloride ion.
In clinical use all thiazide diuretic agents are considered to be of equal effectiveness, both as diuretics and as antihypertensive agents. Although the specific daily dosage will vary for different thiazide compounds and some have a longer half-life than others, and some may cause different levels of chloride ion loss, there is no evidence that these agents differ either in their safety or in their basic mode of action from the prototype compound, chlorothiazide. The adverse effects, especially those involving potassium depletion and patient morbitidy are observed with all of the members of this class.
It has been proposed that the diuretic potency of the thiazide group, which ranges in activity from chlorothiazide being one and cyclopenthiazide as a thousand, is correlated with lipid-solubility of the respective compound and is inversely related to renal clearance of the agent. The observation that a thiazide acts on different receptor sites of the kidney to cause specific actions and pharmacologic responses raises the question that these compounds may also act on systemic receptor sites to cause other systemic actions which as yet remain unknown. The current clinical use of these diuretic compounds in the management of hypertension is solely directed toward achieving high urinary output.